COX-2 and p53 interactions and cancer prevention

描述(由申请人提供)： 环氧合酶2(COX-2)在人类恶性肿瘤中过表达，是开发新的化学预防策略的一个有前途的靶点。目前正在进行临床试验，以调查COX-2选择性非类固醇抗炎药在预防各种类型癌症中的疗效。然而，关于COX-2选择性药物如何介导化学预防作用，仍有许多有待阐明的问题。更好地了解调控COX-2表达的分子机制肯定会有助于开发更有效、毒性更低的癌症预防策略。在这方面，肿瘤抑制因子P53被发现促进COX-2mRNA和蛋白水平的上调。COX-2参与了正向生长调节和肿瘤发生，而抑癌基因P53则是负向生长调节因子。因此，依赖于P53的COX-2的上调似乎相当不一致。已有研究表明，P53依赖的COX-2上调可能是减弱P53诱导细胞凋亡的机制之一。在这项为期两年的先导研究中提出的工作将直接评估P53依赖的COX-2上调是一种代偿反应的假设，该反应有助于减弱P53诱导的细胞凋亡。为了实现我们的目标，我们提出了两个具体目标。在特定的目标1中，我们将研究COX-2是否对野生型P53的功能产生负面影响。我们将建立四环素或多西环素诱导的COX-2和P53双诱导细胞，以研究COX-2是否对野生型P53的功能产生负面影响。通过使用同时诱导COX-2和P53的双诱导细胞，我们将确保从一开始就有更高水平的COX-2可用。因此，如果COX-2对野生型P53的功能产生负面影响，那么它将立即可用于调节其对P53的影响。在特定的目的2中，我们将通过RNA干扰的方法来抑制COX-2的表达，以检测COX-2缺失对包括P53诱导的细胞凋亡在内的P53功能的影响。因此，研究控制COX-2和P53活性相互作用的分子机制是相关的，如果结果成功，将提高我们对恶性肿瘤发生和发展的理解，进一步推动开发新的、更有效和毒性更低的癌症预防策略的进展。

DESCRIPTION (provided by applicant): Cyclooxygenase 2 (COX-2) is overexpressed in human malignancies and is a promising target to develop novel chemopreventive strategies. Clinical trials are currently in progress to investigate the efficacy of COX-2 selective non-steroidal anti-inflammatory drugs in the prevention of various types of cancers. However, much remains to be elucidated as to how COX-2-selective agents mediate chemopreventive effects. A better understanding of the molecular mechanisms that regulate COX-2 expression will certainly facilitate the development of more effective and less toxic cancer-preventive strategies. In this regard, the tumor suppressor p53 has been found to promote upregulation of COX-2 mRNA and protein levels. COX-2 has been implicated in positive growth regulation and tumorigenesis while tumor suppressor p53 is a negative regulator of growth. Thus, p53-dependent upregulation of COX-2 appears rather incongruous. It has been proposed that p53-dependent COX-2 upregulation could be a mechanism to abate the apoptotic effects of p53. The work proposed in this two-year pilot study will directly evaluate the hypothesis that p53-dependent COX-2 upregulation is a compensatory response that serves to abate the p53-induced apoptosis. In order to accomplish our goals, we have proposed two specific aims. In Specific Aim 1, we will investigate whether COX-2 negatively affects the function of wild type p53. We will establish tetracycline or doxycycline-inducible COX-2 and p53 double-inducible cells to investigate whether COX-2 negatively affects the function of wild type p53. By using the double-inducible cells that would exhibit simultaneous induction of COX-2 and p53, we will ensure that higher levels of COX-2 are available from the beginning. Thus, if COX-2 negatively affects the function of wild type p53 then it will be instantly available to mediate its effect on p53. In Specific Aim 2, we will abrogate COX-2 expression via RNA interference approach to test the effect of COX-2 deficiency on p53 functions including p53-induced apoptosis. Thus, investigating the molecular mechanisms that control the interplay between COX-2 and p53 activities is relevant and the outcome, if successful, would improve our understanding of the malignant development and progression to further the progress in developing novel, more effective and less toxic cancer-preventive strategies.